Piracetam (technically known as 2-oxo-pyrrolidone) was developed in the mid-1960’s by UCB pharmaceutical company of Belgium. It was originally used to treat motion sickness. (1) Between 1968 and 1972, however, there was an explosion of Piracetam research which uncovered its ability to facilitate learning, prevent amnesia induced by hypoxia and electroshock, and accelerate electroencephalograph return to normal in hypoxic animals. (1) By 1972 700 papers were published on Piracetam. (1) Yet already by 1972 Piracetam’s pharmacologic uniqueness led C.E. Giurgea, UCB’s principal Piracetam researcher and research coordinator, to formulate an entirely new category of drugs to describe Piracetam: the nootropic drug. (2)

According to Giurgea, nootropic drugs should have the following characteristics:

1) they should enhance learning and memory.
2) They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
3) They should protect the brain against various physical or chemical injuries (e.g. barbiturates, scopalamine).
5) They should ”increase the efficacy of the tonic cortical/subcortical control mechanisms.”
6) They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity. (3)

As research into Piracetam and other nootropics (e.g. pyritinol, centrophenoxine, oxiracetam, idebenone) progressed over the past 30 years, section 5) of Giurgea’s original definition has been gradually dropped by most researchers. (3) Nonetheless, the nootropic drugs represent a unique class of drugs, with their broad cognition enhancing, brain protecting and low toxicity/ side effect profiles. It is an interesting comment on the AMA/FDA stranglehold on American medicine that as of January 2001, not a single nootropic drug has ever been given FDA approval for use in the U.S.

Piracetam has been used experimentally or clinically to treat a wide range of diseases and conditions, primarily in Europe. (Although much of the research on Piracetam has been published in English, a large amount of Piracetam research has been published in German, French, Italian, and Russian.)

Piracetam has been used successfully to treat alcoholisrn/ alcohol withdrawal syndrome in animals and man. (4,5,19) Piracetam has brought improvement, or slowed deterioration, in “senile involution” dementia and Alzheimer’s disease. (6,7) Piracetam has improved recovery from aphasia (speech impairment) after stroke. (8) Piracetam has restored various functions (use of limbs, speech, EEC, slate of consciousness) in people suffering from acute and chronic cerebral ischemia (decreased brain blood flow). (9,10) Piracetam has improved alertness, co-operation, socialization, and IQ in elderly psychiatric patients suffering from “mild diffuse cerebral impairment.” (11)

Piracetam has increased reading comprehension and accuracy in dyslexic children. (8,12) Piracetam increased memory and verbal learning in dyslexic children, as well as speed and accuracy of reading, writing and spelling. (13,14) Piracetam potentiated the anticonvulsant action of various anti-epileptic drugs in both animals and man, while also eliminating cognitive deficits induced by anti-epileptic drugs in humans. (15,16) Piracetam has improved mental performance in “aging, nondeteriorated individuals” suffering only from “middle-aged forgetfulness.” (17) Elderly outpatients suffering from “age-associated memory impairment” given Piracetam showed significant improvement in memory consolidation and recall. (8) Piracetam reversed typical EEC slowing associated with “normal” and pathological human aging, increasing alpha and beta (fast) electroencephalograph activity and reducing delta and theta (slow) electroencephalograph activity, while simultaneously increasing vigilance, attention and memory. (17A)

Piracetam reduced the severity and occurrence of major symptoms of “post-concussional syndrome,” such as headache, vertigo, fatigue and decreased alertness (18), while it also improved the state of consciousness in deeply comatose hospitalized patients following head injuries. (19) Piracetam has successfully treated motion sickness and vertigo. (1) Piracetam “is one of the best available drugs for treating myoclonus [severe muscle spasms] of cortical origin.” (20) Piracetam has successfully treated Raynaud’s syndrome (severe vasospasm in hands and/or feet), with “a rapid and marked improvement. The efficacy of Piracetam has been maintained in several patients already followed for 2-3 years.” (21) Piracetam has been used to inhibit sickle cell anemia, both clinically and experimentally. (11) Piracetam has improved Parkinson’s disease, and may synergize with standard L-dopa treatment. (1) A key part of Piracetam’s specialness is its amazing lack of toxicity. Piracetam has been studied in a wide range of animals: goldfish, mice, rats, guinea pigs, rabbits, cats, clogs, marmosets, monkeys, and humans. (1,19) In acute toxicity studies that attempted to determine Piracetam’s “LD50″ (the lethal dose which kills 50% of test animals), Piracetam failed to achieve an LD50 when given to rats intravenously at 8gm/kg bodyweight. (1) Similarly, oral LD50 studies in mice, rats, and dogs given 10gm Piracetam/kg bodyweight also produced no LD50! (1) This would he mathematically equivalent to giving a 70 kg (154 pound) person 700gm (1.54 pounds) of Piracetam! As Tacconi and Wurtman note, ”Piracetam apparently is virtually non-toxic. Rats treated chronically with 100 to 1,000 mg/kg orally for 6 months and dogs treated with as much as 10g/kg orally for 1 year did not show any toxic effect. No teratogenic (birth deformity) effects were found, nor was behavioral tolerance noted.” (22) Thus, Piracetam must be considered one of the toxicologically safest drugs ever developed.

From the earliest days of Piracetam research, the ability of Piracetam to partly or completely prevent or reverse the toxic action of a broad array of chemicals and conditions has been repeatedly demonstrated. Paula-Barbosa and colleagues discovered that long-term (12 month) alcohol-feeding to rats significantly increased formation of lipofuscin (an age-related waste pigment) in brain cells. Giving high dose Piracetam to the alcohol-fed rats reduced their lipofuscin levels significantly below both the control and alcohol/no Piracetam rats’ levels. (4) Piracetam antagonized the normally lethal neuromuscular blockade (which halts breathing) induced by mice by intravenous hemicholinium-3 (HC-3) (23), and Piracetam also blocked the lethal neuromuscular blockade induced in cats by d-tubocurarine. (1) Piracetam reversed learning and memory deficits in mice caused by the anti-cholinergic substance, HC-3. (23) When mice were given oxydipentonilim, a short-acting curare-like agent which halts breathing, at a dose sufficient to kill 90% of one group and 100% of another group of placebo-treated controls, the two groups of Piracetam-treated mice had a 90% and 100% survival rate. (19)

Rapid synthesis of new protein in brain cells is required for memory formation. Piracetam has ameliorated the amnesia induced by rodents by cycloheximide, a protein synthesis inhibitor. (1)

Hexachlorophene is a toxic chemical that induces edema, membrane damage, and increased sodium /decreased potassium in brain cells. (Hexachlorophene was used in shampoos, soaps and other personal care products until about a decade ago.) Rats were fed hexachlorophene orally for 3 weeks, then given Piracetam or one of 5 other drugs by injection for 6 days. Hexachlorophene seriously disrupted the rats’ ability to navigate a horizontal ladder without frequently falling off the rungs. Piracetam reduced the fall rate 75% compared to saline-injected controls on the first day of treatment. None of the other drugs came close to that improvement. (24)

Piracetam increases the survival rate of rats subjected to severe hypoxia. (1,25) When mice, rats and rabbits have been put under diverse experimental hypoxic (low oxygen) conditions, Piracetam has acted to attenuate or reverse the hypoxia-induced amnesia and learning difficulties, while speeding up post-hypoxic recovery time and reducing time to renormalize the EEC}. (1,2,25) When a single 2400mg dose of Piracetam was given to humans tested under 10.5% oxygen (equivalent to 5300m./17,000 ft. altitude), eye movement reflexes were enhanced, while breathing rate and choice reaction time were reduced by Piracetam. (26)

Electro convulsive shock (electro convulsive shock) is a powerful disruptor of learning and memory. When a group of rats were taught to avoid a dark cubicle within their cage there was 100% retention of the learned behavior 24 hours later.

Giving a maximal electro convulsive shock right after learning caused the learning-retention rate to drop lo 20% 24 hours later in the control group, while Piracetam-treated electro convulsive shock rats still had a 100% retention of the avoidance behavior 24 hours later. (2) Other experiments with mice and rats show Piracetam’s ability to attenuate or reverse electro convulsive shock-induced amnesia. (19.27)

When given the fast acting barbiturate secobarbital, combined with Piracetam injected 1 hour before the secobarbital, 10 of 10 rabbits survived, with only minimal abnormalities in their electroencephalograph records. The electroencephalograph records the electrical activity of large groups of corticol neurons, and also reflects cerebral oxygen/glucose metabolism and blood flow. (25)

Only 3 of 10 rabbits given) secobarbital with saline injection survived, and most of that groups’ electroencephalograph records showed rapid onset of electrical silence, followed quickly by death. When secobarbital was given to rabbits combined with oral Piracetam, 8 of 9 survived, with only 3 of 9 saline-fed controls surviving. The electroencephalograph records of both groups were similar to those of the rabbits given i.v. Piracetam and saline. (28)

By the 1980s neuroscientists had discovered that brain cholinergic neural networks, especially in the cortex and hippocampus, are intimately involved in memory and learning. Normal and pathological brain aging, as well as Alzheimer’s-type dementia were also discovered lo involve degeneration of both the structure and function of cholinergic nerves, with consequent impairment of memory and learning ability. (29)

During this same period a growing body of evidence began to show that Piracetam works in part through a multimodal cholinergic activity. Studies with both aged rats and humans which combined Piracetam with either choline or lecithin (phosphatidyl choline), found radically enhanced learning abilities in rats, and produced significant improvement in memory in Alzheimer’s patients. (30-35)

Yet giving choline or lecithin alone (they are precursors for the neurotransmitter acetylcholine) in these studies provided little or no benefit, while Piracetam alone provided only modest benefit.

Animal research has also shown that Piracetam increases high-affinity choline uptake, a process that occurs in cholinergic nerve endings which facilitates acetylcholine formation. (23,29) “High-affinity choline uptake rate has been shown to be directly coupled to the impulse flow through the cholinergic nerve endings and it is a good indicator of acetylcholine utilization nootropic drugs (including Piracetam) activate brain cholinergic neurons” (29) HC-3 induces both amnesia and death through blocking high-affinity choline uptake in the brain an din peripheral nerves that control breathing. Since Piracetam blocks HC-3 asphyxiation death and amnesia, this is further evidence of Piracetam’s pro-high-affinity choline uptake actions. (23,29)

Scopalamine is a drug that blockades acetylcholine receptors and disrupts energy metabolism in cholinergic nerves. When rats were given Scopalamine, it prevented the learning of a passive avoidance task, and reduced glucose utilization in key cholinergic brain areas. When rats given Scopalamine were pretreated with 100/kg Piracetam, their learning performance became almost identical to rats not given Scopalamine. (36) The Piracetam treatment also reduced the Scopalamine depression of glucose-energy metabolism in the rats’ hippocampus and anterior cingulate cortex, key areas of nerve damage and glucose metabolism reduction in Alzheimer’s disease.(36)

German researchers added to the picture of Piracetam’s cholinergic effects in 1988 and 1991. Treatment for 2 weeks with high dose oral Piracetam in aged mice elevated the density of frontal cortex acetylcholine receptors 30-40%, restoring the levels to those of healthy young mice. A similar decline in cortex acetylcholine receptors occurs in “normal” aging in humans. (37) The same group of researchers then discovered that there is a serious decline in the functional activity of acetylcholine receptors in aged mice; with many receptors becoming “desensitized” and inactive. Oral treatment with high dose Piracetam also partially restored the activity of acetylcholine cortex nerves, as measured by the release of their “second messenger,” inositol-1-phosphate. (38)

Glutamic acid (glutamate) is the chief excitatory neurotransmitter in the mammalian brain. Piracetam has little affinity for glutamate (glutamate) receptors, yet it does have various effects on glutamate neurotransmission. One subtype of glutamate receptor is the AMPA receptor. Micromolar amounts [levels which are achieved through oral Piracetam intake] of Piracetam enhance the efficacy of AMPA-induced calcium influx [which "excites" nerve cells to fire] in cerebeller [brain] cells. Piracetam also increases the maximal density of [AMPA glutamate receptors] in synaptic membranes from rat cortex due to the recruitment of a subset of AMPA receptors which do not normally contribute to synaptic transmission.” (1) Further support for involvement of the glutamate system in Piracetam’s action is provided by a Chinese study which showed that the memory improving properties of Piracetam can be inhibited by ketamine, an NMDA (another major subtype of glutamate receptor) channel blocker. (1) Furthermore, high dose injected Piracetam decreases mouse brain glutamate content and the glutamate/GABA ratio, indicating an increase in excitatory nerve activity (1)

At micrornolar levels, Piracetam potentiates potassium-induced release of glutamate from rat hippocampal nerves. (1)

Given that acetylcholine and glutamate are two of the most central “activating” neurotransmitters and the facilatory effects of acetylcholine/glutamate neural systems on alertness, focus, attention, memory and learning. Piracetam’s effects on acetylcholine/glutamate neurotransmission must he presumed to play a major role in its demonstrated ability to improve mental performance and memory. Although Piracetam is generally reported to have minimal or no side effects, it is interesting to note that Piracetam’s occasionally reported side effects of anxiety, insomnia, agitation, irritability and tremor (18) are identical to the symptoms of excess acetylcholine/glutamate neuroactivity.

In spite of the many and diverse neurological/psychological effects Piracetam has shown in human, animal and cell studies, Piracetam is generally NOT considered to he a significant agonist (direct activator) or inhibitor of the synaptic action of most neurotransmitters. Thus, major nootropic researchers Pepeu and Spignoli report that “the pyrrolidinone derivatives [Piracetam and other racetams] show little or no affinity for central nervous system receptors for dopamine, glutamate; serotonin, GABA or benzodiazepine.” (23) They also note however that “a number of investigations on the electrophysiological actions of nootropic drugs have been carried out. Taken together, these findings indicate that the nootropic drugs of the [Piracetam-type] enhance neuronal excitability [electrical activity] within specific neuronal pathways.” (23)

Grau and colleagues note that “there exist papers giving data of bioelectric activity as affected by Piracetam, and suggesting that it acts as a non-specific activator of the excitability. [i.e. brain electrical activity] thus optimizing the functional state of the brain.” (25)

Gouliaev and Senning similarly state “we think that the racetams exert their effect on some species [of molecule] present in the cell membrane of all excitable cells, i.e. the ion carriers or ion channels and that they somehow accomplish an increase in the excitatory (electrical) response. It would therefore seem that the racetams act as potentiators of an already present activity (also causing the increase in glucose utilization observed), rather than possessing any [neurotransmitter-like] activity of their own, in keeping with their very low toxicity and lack of serious side effects. The result of their action is therefore an increase in general neuronal sensitivity toward stimulation.” (1)

Thus Piracetam is NOT prone to the often serious side effects of drugs which directly amplify or inhibit neurotransmitter action e.g. MAO inhibitors; Prozac® style “selective serotonin reuptake inhibitors”, tricyclic antidepressants, amphetamines, Ritalin®, benzodiazepines (Valium), etc.

A key finding on Piracetam in various studies is its ability to enhance brain energy, especially under deficit conditions. Energy (ATP) is critical to the brain’s very survival; it typically uses 15-20% of the body’s total ATP production, while weighing only 2-3% or so of bodyweight. Brain cells must produce all their own ATP from glucose (sugar) and oxygen - they cannot “borrow” ATP from other cells. Branconnier has observed that “evidence from studies of cerebral blood flow, oxygen uptake and glucose utilization have shown that brain carbohydrate metabolism is impaired in a variety of dementias and that the degree of reduction in brain carbohydrate metabolism is correlated with the severity of the dementia.” (39) In a 1987 study, Grau and co-workers gave saline or Piracetam i.v. to rats who were also fed i.v. radioactive deoxygilicose to help measure brain metabolism. Compared to saline controls, Piracetam rats had a 22% increase in whole brain glucose metabolism, while the increase in 12 different brain regions ranged from L6 to 28%. (25) This increase in brain energy metabolism occurred under normal oxygen conditions.

In 1976 Nickolson and Wolthuis discovered that Piracetam increased the activity of adenylate kinase in rat brain. Adenylate kinase is a key energy metabolism enzyme that converts ADP into ATP and AMP and vice versa. It comes into play especially when low brain oxygen begins to reduce mitochondrial ATP production. As existing ATP is used up, ADP is formed. Under the influence of adenylate kinase, 2ADP becomes ATP plus AMP. Thus Piracetam-activated adenylate kinase can slow down the drop in ATP in oxygen-compromised brains. This helps explain Piracetam’s ability to prevent abnormalities in animals subjected to hypoxia or barbiturates. When oxygen levels return toward normal, adenylate kinase can convert AMP into ADP, which can then be used in the reactivated mitochondria to make more ATP. This accounts for the ability of Piracetam to speed up recovery from hypoxia seen in animal studies. (40)

In their 1987 study with rats, Piercey and colleagues found that Piracetam could restore scopalamine depressed energy metabolism modestly in many brain areas, and significantly in the hippocampus and anterior cingulate cortex. (36)

Piracetam has also been shown to increase synthesis and turnover of cytochrome b5, a key component of the electron transport chain, wherein most ATP energy is produced in mitochondria. (22) Piracetam also increases permeability of mitochondrial membranes for certain intermediaries of the Krebs cycle, a further plus for brain ATP production. (25) In his 1989 paper on cerebral ischemia in humans, Herrschaft notes that the Herman Federal Health Office has conducted controlled studies that indicate a “’significant positive” effect of Piracetam (4.8 - 6gm/day) to increase cerebral blood flow, cerebral oxygen usage metabolic rate and cerebral glucose metabolic rate in chronic impaired human brain function - i.e. multi-infarct dementia, senile dementia of the Alzheimer type, and pseudo-dementia. (9)

The cerebral cortex in humans and animals is divided into two hemispheres, the left and right cortex. In most humans the left hemisphere (which controls the right side of the body) is the language center, as well as the dominant hemisphere. The left cortex will tend to be logical, analytical, linguistic and sequential in its information processing, while the right cortex will usually be intuitive, holistic, picture-oriented and simultaneous in its information processing.

Research has shown that most people favor one hemisphere over the other, with the dominant hemisphere being more electrically active and the non-dominant hemisphere relatively more electrically silent, when a person is being tested or asked to solve problems or respond to information. The two cortical hemispheres are linked by a bundle of nerve fibers: the corpus callosum and the anterior commisure. In theory these two structures should unite the function of the two hemispheres. In practice they act more like a wall separating them.

From a neurological perspective, the cerebral basis for a well-functioning mind would he the effective, complementary, simultaneous integrated function of both cortical hemispheres, with neither hemisphere being automatically or permanently dominant. This in turn would require the corpus callosum and cerebral commisure to optimize information flow between the two hemispheres. Research has shown Piracetam to facilitate such inter-cerebral information transfer-indeed, it’s part of the definition of a “nootropic drug.”

Giurgea and Moyersoons reported in 1972 that Piracetam increased by 25 to 100% the transcallosal evoked responses elicited in cats by stimulation of one hemisphere and recorded from a symmetrical region of the other hemisphere. (41) Buresova and Bures, in a complex series of experiments involving monocular (one-eye) learning in rats, demonstrated that “Piracetarn enhances transcommisural encoding mechanisms and some forms of inter-hemispheric transfer.” (42)

Dimond and co-workers used a technique called “dichotic listening” to verily the ability of Piracetam to promote interhemispheric transfer in humans. In a dichotic listening test, different words are transmitted simultaneously into each ear by headphone. In most people the speech center is the left cortex. Because the nerves from the ears cross over to the opposite side of the brain, most people will recall more of the words presented to the right ear than the left ear. This occurs because words received by the right ear directly reach the left cortex speech center, while words presented to the left ear must reach the left cortex speech center indirectly, by crossing the corpus callosum from the right cortex. Dimond’s research with healthy young volunteers showed that Piracetam significantly improved left ear word recall, indicating Piracetam increased interhemispheric transfer. (43)

Okuyama and Aihara tested the effect of aniracetam, a Piracetam analog, on the transcallosal response of anaesthetised rats. The transcallosal response was recorded from the surface of the frontal cortex following stimulation of the corresponding site on the opposite cortical hemisphere. The researchers reported that “the present results indicate that Piracetam…increased the amplitude of the negative wave, thereby facilitating inter-hemispheric transfer. Thus, it is considered that the functional increase in interhemispheric neuro-transmission by nootropic drugs may be related to the improvement of the cognitive function [that nootropics such as Piracetam and aniracetam promote].” (44)

The notable absence of biochemical, physiological, neurological or psychological side effects, even with high dose and/or long-term Piracetam use, is routinely attested to in the Piracetam literature. Thus in their 1977 review Giurgea and Salama point out: “Piracetam is devoid of usual ‘routine’ pharmacologic activities [negative side effects] even in high doses. In normal subjects no side effects or ‘doping’ effects were ever observed. Nor did Piracetam induce any sedation, tranquilization, locomotor stimulation or psychodysleptic symptomatology.” (19) Wilshen and colleagues, in their study on 225 dyslexic children, note that “Piracetam was well tolerated, with no serious adverse clinical or laboratory effects reported.” (12) In this particular study (as in many others), the incidence of (mild) side effects was higher in the placebo group than in the Piracetam group! In his 1972 8 week study on 196 patients with “senile involution” dementia, Stegink reported that “No adverse side effects of Piracetam [2.4gm/day] were reported.” (6) In their study of 30 patients treated for one year with 8gm Piracetam/day, Croisile and colleagues observed that “Few side effects occurred during the course of the study - one case of constipation in the Piracetam group…. Piracetam had no effect on vital signs, and routine tests of renal, hepatic, and hematological functions remained normal. No significant changes in weight, heart rate, or blood pressure occurred….” (7)

Yet as noted in the section on glutamate, because Piracetam is a cholinergic/glutamatergic activator, there is the potential for symptoms related to cholinergic/glutamatergic excess to occur, especially in those unusually sensitive to Piracetam. Such symptoms - anxiety, insomnia, irritability, headache, agitation, nervousness, and tremor - are occasionally reported in some people taking Piracetam. (11,18) Reducing dosage, or taking magnesium supplements (300-500mg/day), which reduce neural activity, will frequently alleviate such “overstimulation” effects. Persons consuming large amounts of MSG (monosodium glutamate) and/or aspartame in their diet should be cautious in using Piracetam, as should those who are highly sensitive to MSG-laden food (the “Chinese restaurant syndrome”). Caffeine also potentiates Piracetam’s effects, as do other nootropics such as deprenyl, idebenone, vinpocetine, and centrophenoxine, and it may be necessary to use Piracetam in a lower dosage range if also using any of these drugs regularly. Those wishing to augment Piracetam’s cholinergic effects may wish to combine it with cyprodenate or centrophenoxine, which are much more powerful acetylcholine enhancers than choline or lecithin.

B complex vitamins, NADH, lipoic acid, Co Q10, or idebenone, and magnesium will enhance Piracetam’s brain energy effects. In the clinical literature on Piracetam, dosages have ranged from 2.4 gm/day (6,11) up to 8gm/day (7,21), continued for years (7,21). Piracetam has a relatively short half-life in the blood, although there is some short-term bioaccumulation in the brain. (1,22) Piracetam is therefore usually taken 3-4 times daily. 1.6 gm, 3 times daily, or 1.2 gm 3-4 times daily is a fairly typical Piracetam dosage, although some people report noticeable improvement in memory and cognition from just 1.2 gm twice daily.

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Over 30 years have passed since the “Nootropic Revolution” quietly began with the development of Piracetam in the late medical efficacy with a virtual absence of toxicity and side effects; something rarely seen with more standard medical drugs.

More importantly, they offered promise not only in the realm of fighting disease, but also in the virtually unexplored realm of drugs that could not only postpone or even reverse “normal” brain aging, but could even make “normal” brains work better!

The Piracetam-nootropics have been exhaustively researched; since the first scientific studies on Piracetam in the late 1960’s over 1000 scientific papers on Piracetam, Oxiracetam, Pramiracetam, and Aniracetam have been published with about two thirds of them on Piracetam.

The action of the Piracetam-nootropics has been studied in a broad range of animals; goldfish, mice, rats, guinea pigs, rabbits, cats, dogs, marmosets, monkeys and humans.

The toxicity of Piracetam and its “cousins” is amazingly low- almost non-existent. In acute toxicity studies, intravenous doses of Piracetam given to rats (8g/ Kg bodyweight) and oral doses given to mice, rats, and dogs (10g/ Kg or more) produced no toxicity.

This would be equivalent to 560-700 grams (1.23 to 1.54 pounds) for a 154 pound human. Rats given 100-1000mg/ Kg orally for 6 months and dogs given 10,000mg/ Kg orally for one year showed no toxic effect, a teratogenic (birth defect causing) effects were found, either (Tacconi and Wurtman 1986).

The Piracetam-nootropics are among the toxicologically safest drugs ever developed.

The four main commercially available “racetam” nootropics all share a pyrrolidine nucleus, while Piracetam, Oxiracetam, and Pramiracetam, also share an acetyl group. The racetams (especially Piracetam and Oxiracetam) are closely related in structure to the amino acid Pyroglutamic Acid. Pyroglutamic Acid has been shown in some studies to have weak nootropic activity (Gouliaev and Senning 1994). Pyroglutamic Acid is naturally present in many human foods, as well as the mammalian brain.

The concept and definition of a “nootropic drug” was first proposed in 1972 by C.E. Giurgea, the principal Piracetam researcher and research coordinator for UCB, the Belgian company that launched Piracetam. “The main features… defining a nootropic drug are

(A) the enhancement, at least under some conditions, of learning acquisitions as well as the resistance of learned behaviors to agents that tend to impair them;

(B) the facilitation of interhemispheric flow of information;

(C) the partial enhancement of the general resistance of the brain and particularly its resistance to physical and chemical injuries;

(D) the increase in the efficacy of the tonic cortico-subcortical control mechanisms; and

(E) [absence of the usual negative pharmacologic effects of psychotropic drugs].

” Giurgea,and Salama 1977). Giurgea derived the term “nootropic” from the i words “noos” (=mind) and “tropein” (=to turn toward).

Schaffler and Klausnitzer (1988) have given an excellent brief overview of some of the chief effects of the Piracetam-nootropics. “From animal biochemistry it is known that [Piracetam-nootropics] enhance brain metabolism by stimulation of oxidative catabolism, increase of ATP-turnover and cAMP levels, enhancement of phospholipid-metabolism and protein biosynthesis. [Piracetam-nootropics have] an impact on the hippocampal release of acetylcholine and on the dopaminergic turnover, too. Pharmacologically there exist protective effects with regard to several noxes [harmful agents] and an impact on the associative cortical sphere and on hippocampal structures, which are related with learning and memory, especially when the respective functions are impaired. The performatory enhancements are related with an increased arousability of hippocampal pyramid cells, facilitated transmission of the thalamic afferences, increased release of hippocampal acetylcholine and enhanced synaptic transmission.

The clinical biochemistry indicates enhancing functions on the utilization of oxygen and glucose under the conditions of decreased brain metabolism, as well as improvements in local perfusion. Due to this profile [Piracetam-nootropics] can be expected to be of value in the treatment of disease which are related to impairments in the above mentioned features, such as several types of senile dementia, (e.g. Primary Degenerative Dementia= Alzheimer’s type: Multi Infarct [stroke] Dementia), ischemic [poor brain blood flow] insults, hypoxia, anoxia and toxicologically or dietary based deficiencies.” (Footnotes in the original text omitted here).

From the beginning of Piracetam research, the ability of the Piracetam-nootropics to partly or completely prevent or reverse the toxic action of a broad array of chemicals and conditions has been repeatedly demonstrated. Aniracetam reverses the memory impairment in rats induced by Clonidine. Piracetam, Oxiracetam, Pramiracetam, and Aniracetam all antagonize the normally lethal neuromuscular blockade induced by Hemicholinium-3 (HC3) in mice. Piracetam, Oxiracetam, and Aniracetam have all attenuated or reversed the Scopalamine (anticholinergic agent)- induced amnesia in rats and mice under a broad range of experimental conditions.

Oxiracetam has reversed the typical “spaced out” electroencephalogram of healthy humans given Valium, restoring a normal vigilance electroencephalogram while maintaining Valium’s anti-anxiety effects. Piracetam and Aniracetam have ameliorated the amnesia produced by the protein synthesis inhibitor Cycloheximide.

Piracetam, Oxiracetam, Pramiracetam, and Aniracetam all attenuate or reverse the amnesia in mice and rats induced by electroconvulsive shock treatment in both passive and active learning conditions.

When mice were given Oxydipentonium, a short acting curare-like agent which induces asphyxia, at a dose sufficient to kill 90-100% of the placebo treated controls, the two groups of Piracetam treated mice had a 90 and 100% survival rate.

When humans, rats, mice and rabbits have been put under diverse hypoxic experimental conditions, Piracetam, Oxiracetam, and Aniracetam have acted to attenuate or reverse the hypoxia-induced amnesia and learning difficulties. as well as to speed up recovery time from hypoxia and reduce the time needed to renormalize the electroconvulsive shock treatment (Gouliaev and Senning Giurgea and Salama 1977).

A classic series of experiments on the protective power of Piracetam against barbiturate poisoning was reported by Moyersoons and Giurgea in 1974. Rabbits connected to electroconvulsive shock treatment machines were given either Piracetam or saline injections before intravenous (I.V.) administration of the fast acting barbiturates-Secobarbital.

When Piracetam was given I.V. one hour before Secobarbital, 10/10 rabbits survived versus 3/10 survivors given saline. Electroconvulsive shock treatment records showed only minimal abnormalities in the Piracetam rabbits, while the saline rabbits showed massive electroconvulsive shock treatment silence, rapidly followed by death. When given only one-half hour before Secobarbital, 7/11 Piracetam rabbits survived versus 3/1 1 control rabbits.

Electroconvulsive shock treatment records of the Piracetam rabbits showed somewhat more abnormalities than those given one hour Piracetam pre-treatment, but still far more normal appearing than the saline control rabbits’ electroconvulsive shock treatment. Piracetam was also given orally one hour before Secobarbital. 8/9 Piracetam rabbits survived while only 3/9 controls survived. The electroconvulsive shock treatment records of both groups were similar to those of the rabbits given Piracetam and saline I.V. one hour before Secobarbital.

The experiments then treated Piracetam against a more slow acting barbiturate Allobarbital, giving the Piracetam I.V. two minutes after the Allobarbital infusion 11/13 Piracetam rabbits survived, while only 2/13 saline control rabbits survived electroconvulsive shock treatment. Records of the Piracetam rabbits again showed electrical silences to be almost absent, and if present, to be shorter and appear later than in the control animals.

In the Allobarbital experiment, one of the two surviving control rabbits actually presented a more normal electroconvulsive shock treatment after Allobarbital than did one of the survivors eleven Piracetam survivors..

Yet an electroconvulsive shock treatment recorded the next morning (about 18 hours later) showed that the control was still asleep, and it was not aroused by a loud noise. The Piracetam rabbit, however, was well awake, behaved normally, moved around and its electroconvulsive shock treatment was normal.

Thus, whether given I.V. or orally, and before or after general lethal (to controls) barbiturate infusion, Piracetam served to protect both life and brain structure and function, as evidenced by electroconvulsive shock treatment records and post recovery behavior.

The rabbit experiments just described are hardly unusual. The Piracetam-nootropics routinely show an ability to stabilize or normalize the electroconvulsive shock treatment’s of humans and animals under a broad range of experimental and medical conditions.

The electroconvulsive shock treatment records the electro-chemical activity of large groups of cortical neurons, and thus provides a “macro” picture of brain activity. Aging, dementia, hypoxia and benzodiazepines all promote a similar shift in electroconvulsive shock treatment frequency patterns.

Low frequency delta waves (0-4 cycles per second) and theta waves (4-8 cps) are increased, while alpha waves (8-12 cps) and beta waves (beta-1; 12-20 cps, beta 2; 20-32 cps) diminish. The average frequency of the delta and alpha waves also drops, as compared to healthy normal subjects.

Nootropics - clinical studies

Giaguinto and colleagues (1986) gave 12 healthy humans 5mg Valium orally at 10PM the night before their experiment. The next morning they were given either I.V. Oxiracetam or saline in a double blind crossover experiment. Oxiracetam strongly decreased the excessive delta activity while simultaneously strongly increasing alpha activity, and also induced a modest increase in beta activity. Thus Oxiracetam restored the electroconvulsive shock treatment to a pattern indicating increased vigilance and alertness, yet without destroying Valium’s anti-anxiety effect.

Itil and co-workers (1986) treated four groups of 15 patients suffering mild to moderate dementia with either Oxiracetam or placebo for three months. The double blind study used Oxiracetam in doses of 800, 1600 and 2400mg daily. Quantitative electroconvulsive shock treatment data indicated that in patients with dementia, Oxiracetam had a mode of action similar to other vigilance enhancing compounds. The majority of patients who had abnormal slow electroconvulsive shock treatment patterns before treatment showed a “normalization” of their brain waves- i.e. a decrease in slow (delta and theta) and an increase in alpha waves. Saletu and colleagues (1985) conducted a four week double blind trial of Oxiracetam (2400 mg per day) or placebo in 40 patients (mean age; 80 years) suffering from the “organic brain syndrome of late life.” Their results showed a clear trend towards a decrease in delta and theta wave activity, an increase in alpha and beta wave activity, as well as an increase in the dominant frequency and the centroid of alpha activity after Oxiracetam treatment. Their report noted: “The attenuation of the slow activity and the elevation of the alpha and/or slow wave beta activity after [Oxiracetam - other studies have shown similar results with Piracetam and Aniracetam] reflect CNS changes that are just oppositional to those seen in normally and pathologically aging subjects… The increase in delta and theta activities and decrease in alpha activity in normal and pathological aging are due to deficits in the vigilance regulatory systems which can be counteracted by nootropic drugs.”

Nootropics - and the healthy

Piracetam-nootropics have also shown the ability to improve learning and memory in healthy individuals not suffering from disease or severe age-related degeneration. In 1976 Dimond and Brouwers reported the results of some of a series of seven double blind trials, involving 16 second and third year college students “in excellent health and good physical and mental condition.”

Subjects received either 4.8 grams a day Piracetam or placebo for 14 days. In three different measures of verbal learning and memory, the results showed a highly significant difference in favor of the Piracetam students over the controls, with confidence levels of P=.01, P=.02 and P=.01. The authors stated “the fact is that Piracetam improves verbal learning and in this it would appear to be a substance which is.. capable of extending the intellectual functions of man.. our subjects were not senile, suffering from generalized brain disorder, confusional states, or any other pathology of the brain… It is therefore possible to extend the power which [individuals gifted with high intelligence and good memory] possess to still higher levels despite the fact that the range of their achievement is a high.”

Giurgea and Salama report the confirmation of Dimond/ Brouwer’s work by Wedl and Suchenwirth in 1977. Wedl found significant improvement in mental performance in a group of 17 healthy young volunteers given 3.2 grams per day Piracetam for five days.

Mindus and colleagues (1976) reported the results of a double blind crossover trial with 18 healthy middle aged people (median age 56), with no evidence of somatic or mental disease, based on medical records and administration of several intelligence tests (group mean IQ; 120 plus or minus 11).

Most of the subjects were in intellectually demanding jobs, but had reported a slight reduction for some years in their capacity to retain or recall information.

After four weeks of 4.8 grams per day Piracetam, Piracetam subjects were switched to placebo for four weeks, while the original placebo group then received Piracetam for four weeks.

Results of a series of paper and pencil tests, as well as computerized tests to measure perceptual motor reactions, showed a clear benefit of Piracetam over placebo.

The three different paper and pencil tests showed superior effects on performance compared to placebo, with confidence levels of P<.001, P<.001 and P<.05. In four of the six computerized tests Piracetam showed a significant effect over placebo, with confidence levels of P<.05 for three and P<.029 for the fourth.

A fifth test showed a clear trend in favor of Piracetam, with P<.10. Wilsher and co-workers (1979) related their results with 4.8 grams per day Piracetam in a double blind, crossover trial to study the benefits of Piracetam for dyslexic students.

Interestingly, the 14 healthy student controls, matched for IQ with the dyslexic subjects, demonstrated a significantly better result on a test measuring ability to memorize nonsense syllables while using Piracetam as compared to placebo.

Their improvement from baseline was a 19.5% decrease in the number of trials needed to learn the nonsense syllables while using Piracetam, versus a 10.9% decrease from baseline while using placebo. P<.05. Piracetam-nootropics may increase learning and memory in healthy individuals, where they are not merely attenuating or reversing pathology, through their distinctive power to promote what has been termed “hemispheric super-connection.”

The cerebral cortex in humans and animals is divided into two hemispheres- the left and right cortex. In most humans the left hemisphere (which controls the right side of the body) is the language center, as well as the dominant hemisphere. The left cortex will tend to be logical, analytical, linguistic and sequential in its information processing, while the right cortex will usually be intuitive, holistic, picture oriented and simultaneous in its information processing. Research has shown most people favor one hemisphere over the other, with the dominant cortex being more electrically active and the nondominant cortex relatively more electrically silent (when the person is being tested or asked to solve problems, or respond to information). The two cortical hemispheres are linked by a bundle of nerve “cables”; the corpus callosum and the anterior commisure. In theory these two structures should unite the function of the two hemispheres; in practice they act more like a wall separating them. This “functionally-split” neurology produces a parallel set of dichotomies in consciousness; logic vs. intuition; reason vs. emotion; analysis vs. synthesis; parts vs. whole; words vs. pictures; science vs. art and religion, etc. As noted earlier, the word “nootropic” is derived from the Greek word “nous” (the more standard philosophical spelling). Yet in the philosophy of Plato and Aristotle, “nous” did not simply mean “mind.” In ancient Greek philosophy, “nous” referred to the faculty of “higher mind” or “reason,” as opposed to the more concrete, sensory oriented mind which humans share even with the lower animals. And “reason” did not merely mean logic or analysis.

The Greek philosophers saw the role of philosophy to be a method of developing and perfecting nous/ reason. They understood nous/ reason to be the integrative mind, where logic works complementarily with intuition, and reason and emotion are in harmony. With a developed nous, one could clearly see and understand “the forest and the trees” simultaneously. From a modern neurological perspective it is obvious that the cerebral basis for a well-functioning nous would be the effective, complementary, simultaneous integrated function of cortical hemispheres, with neither hemisphere being automatically dominant or silent.

This in turn would require the corpus callosum and anterior commisure to optimize information flow between the two hemispheres. Research has shown the Piracetam-nootropics to facilitate such intercebral information transfer- indeed, it’s part of the definition of a “nootropic drug.”

Giurgea and Moyersoons reported in 1970 that Piracetam increased by 100% the transcallosal evoked responses elicited in cats by stimulation of one hemisphere and recorded from a symmetrical region of the hemisphere.

Buresova and Bures (1976) in a complex series of experiments involving monocular (one-eye) learning in rats, demonstrated that “…Piracetam enhances transcommisural encoding mechanisms… and some forms interhemispheric transfer…”

Dimond (1976, 1979) used a technique called “dichotic listening” to verify the ability of Piracetam to promote interhemispheric transfer in humans. In a dichotic listening test, different words are transmitted simultaneously into each ear by headphone. In most people the speech center is the left cortex, because the nerves from the ears cross over to the opposite side of the brain, most people will recall more of the words presented right ear than the left ear. Words received by the right ear directly reach the left cortex speech center, while words presented to the left ear must reach the left cortex speech center indirectly, by crossing the corpus callosum. Dimond’s experiments with young healthy volunteers showed that Piracetam significantly improved left ear word recall, indicating Piracetam increased interhemispheric information transfer.

Okuyama and Aihara (1988) tested the effect of Aniracetam on the transcallosal response of anaesthetised rats. The transcallosal response was recorded from the surface of the frontal cortex following stimulation of the corresponding site on the opposite cortical hemisphere. Aniracetam at two different I.V. doses (10 mg and 30mg per Kg) significantly increased the amplitude of the negative wave compared to its level prior to drug, P<.01 and P<.001. The researchers stated that “the present results indicate that Aniracetam.. increased the amplitude of the negative wave, thereby facilitating interhemispheric transfer… Thus, it is considered that the functional increase in interhemispheric neurotransmission by nootropic drugs may be related to the improvement of the cognitive function.”

In spite of the many and diverse neurological and psychological benefits they have shown in human, animal and cell studies, the Piracetam-nootropics are generally considered NOT to be major agonists or inhibitors of the synaptic action of most neurotransmitters. Thus, major nootropic researchers Pepeu and Spignoli (1990) state; “the pyrrolidinone derivatives [Piracetam-nootropics] show little or no affinity for CNS receptors for dopamine, glutamate, serotonin, GABA, or benzodiazepine… So far, little effect of nootropic drugs has been demonstrated on brain monoamine and amino acid neurotransmitters’ metabolism and release.”

They also note however that “… a number of investigations on the electrophysiological actions of nootropic drugs have been carried out… Taken together, these findings indicate that the nootropic drugs of the [Piracetam-type] enhance neuronal excitability within specific neuronal pathways.”

Gouliaev and Senning similarly state “… we think that the racetams exert their effect on some species [of molecule] present in the membrane of all excitable cells, i.e. the ion carriers or ion channels and that they somehow accomplish an increase in the excitatory response… It would therefore seem that the racetams act as potentiators of an already present activity (also causing the increase in glucose utilization observed), rather than possessing any activity of their own, in keeping with their very low toxicity and lack of serious side effects. The result of their action is therefore an increase in general ne sensitivity towards stimulation.”

Thus the Piracetam-nootropics would NOT be prone to the (often serious effects of drugs which directly amplify or inhibit neurotransmitter c e.g. MAO inhibitors, Prozac-style “selective serotonin reuptake inhibitors, tricyclic antidepressants, amphetamines, benzodiazepines, etc.

The notable absence of biochemical, physiological, neurotogical, psychological side effects, even with high dose and/ or long term nootropic use, is routinely attested to in the vast literature on them. Thus in their 1977 review Giurgea and Salama point out: “Piracetam active in previously described situations, is devoid of usual ‘re pharmacologic activities even in high doses… In normal subjects.. no side effects or ‘doping’ effects were ever observed. Nor did Piracetam induce any sedation, tranquillization. locomotor stimulation or psychodysleptic symptomatology..”

Itil and co-workers reported in 1983 that “This investigation has confirmed that [Pramiracetam] is a safe and well tolerated compound that can be given in dosages up to 1500 mg without significant side effects. In fact side effects were reported more frequently following both placebo and… phenelzine sulfate [an 'active control' drug] than following any of the four doses evaluated.”

After a major 12 week study with 272 Alzheimer and stroke dementia patients, Maina and colleagues (1989) reported; “Thirty five minor side effects were recorded in 30 patients on [Oxiracetam] and 33 unwanted effects in 26 patients on placebo, but none of these was withdrawn from the study… As far as tolerability is concerned, clinical assessments and laboratory evaluations did not reveal any difference between treatment and placebo].”

Moglia and co-workers (1986) concluded from a study of 43 organic syndrome patients that “side effects during [Oxiracetam] treatment headache (3 cases), constipation (1 case), sleep disturbances (1 Side effects during placebo treatment were headache (2 case constipation (1 case). The side effects spontaneously disappears required neither medication nor treatment interruption. No significant [adverse] change in neurological and laboratory ex( lions, ECG and EEG could be detected at the end of treatment, both in the [Oxiracetam] and in the placebo groups.” When side effects are occasionally reported in the clinical literature on Piracetam-nootropics. they are usually of a type to suggest slight over-stimulation, mainly headaches, agitation, insomnia and irritability. Yet other studies find these same symptoms to be improved by Piracetam-nootropics when these symptoms are pre-existing in the patients. Thus Itil (1986) notes, “…[ Piracetam] showed more improvement than [Oxiracetam] in factors of paranoid delusion and agitation.” Maina (1989) noted that “[Oxiracetam] does not act only by increasing arousal and alertness. If this were the case, there would probably be a worsening of the IPSC-E anxiety and tension [scores]. However, in our study there was actually a decrease in anxiety and tension.” Branconnier (1983), reporting on his group’s study of Pramiracetam in 32 Alzheimer patients noted that after four weeks’ treatment, there was a significant decrease in anxiety-tension (P=.004) and hostility (P=.03), and a clean trend over placebo (P=.08) for Pramiracetam to improve existing sleep disturbances.

One potentially limiting factor in obtaining clinical benefit from Piracetam-nootropics has been bought to light through the research of Mondadori (1992) on steroid interactions with nootropics. Mondadori has shown that either deficient or excessive levels of adrenal steroids can block the memory benefits of Piracetam-nootropics in animals. High doses of either corticosterone or aldosterone abolish the memory enhancing benefits of Piracetam-nootropics, while giving corticosterone or aldosterone to rats with no adrenals restores the positive memory effects of nootropics. Mandadori also notes that cortisol levels are frequently elevated in Alzheimer patients, which might explain the inconsistent results obtained with nootropics in different Alzheimer clinical studies.

Nootropics - Synergy.

Since Piracetam-nootropics act (in part) through subtly amplifying neuronal electrical excitability, they will tend to increase the activity of other drugs that modify neural activity taken simultaneously. This in turn may increase both the positive action of the other drug, as well as possibly lead to the occasional nootropic over-stimulation effects. Thus even caffeine may be sufficiently stimulating to bring on the “nootropic over stimulation effect,” especially in those very sensitive to caffeine. A key normal regulator of neuronal sensitivity is the essential mineral, Magnesium. Dietary surveys in the Western world routinely show most people to be at least marginally Mg deficient, with many getting half or less of the recommended dietary Magnesium intake (Wester 1987).

Thus, the occasional over stimulation seen with Piracetam-nootropics may simply evidence an undetected synaptic Magnesium deficiency, and Magnesium supplementation may provide a natural remedy to minimize such over stimulation Piracetam-nootropics have been combined in many clinical and experimental situations with other drugs, almost always with a positive, synergistic effect. Many clinical experiments have demonstrated Piracetam and Oxiracetam to synergize with anti-epileptic medications, especially carbamazepine (Tegretol). A simultaneous enhancement of the anti-epileptic drug’s anti-seizure activity, combined with improvement or elimination of the memory, alertness and comprehension cognitive deficits induced 1: anti-epileptic drug, have been found in multiple studies (Chaudhry Piracetam combined with Pentoxifylline (a caffeine analogue cerebral flow enhancer) increased both “psycho-intellectual performance measures of cerebral blood flow), significantly more than place either drug alone (Parnetti 1985).

Human and animal studies have shown increased benefit from combining Piracetam with Choline, the raw material for neuronal production of be neurotransmitter Acetylcholine, as well as Phosphatidylcholine, a fluidizing component of cell membranes (Ferris 1982). When Piracetam was combined with Hydergine in experiments with mice both brain survival time and learning/ memory deficits induced poxia, it was noted that “The effect of the combination was greater than the sum of the effects of the individual agents and indicates that synergism had occurred” (Berga 1986). A 1994 report looked at the synergy between Piracetam and intensive speech therapy given to post-stroke aphasic patients; “In general, changes under [Piracetam] were 160% of the changes observed in patients receiving placebo, while getting the same intensive speech therapy” (Di 1994).

Those wishing to get the maximum benefit from Piracetam-nootropics may to include in their regimen nutrients known to enhance brain structure function in various ways.

The B-complex vitamins (including NADH), Lipoic Acid, CoQ10, Magnesium, and Manganese are all essential to brain ATP energy production through the glyolytic and citric acid cycles and the electron transport side chain.

DMAE is an excellent Choline precursor passes the blood brain barrier better than Choline or Lecithin. Acetyl L-carnitine enhances the activity of the enzyme (Choline Acetyl Transferase (CAT) that combines Acetyl groups with Choline to produce Acetylcholine.

Acetyl L-carnitine also renews the structure and energy generating power of aging neuronal mitochondria. Phosphatidylserine is a natural neuronal membrane component and stabilizer. Antioxidants, such as vitamins C and E, as well as Pycnogenol or grape seed extract, may protect polyunsaturated fat-rich neuronal and mitochondrial membranes from the damage caused by the inevitable release of large numbers of free radicals, generated through brain mitochondrial energy production.

Nootropics - their differences

Individual differences of action between Piracetam, Oxiracetam, Pramiracetam, and Aniracetam are often subtle, and in many studies they show similar modes of action. One intriguing benefit I have seen reported only for Pramiracetam, is its ability to increase goal directed and purposive behavior (Branconnier 1983). After trying Pramiracetam in my regimen several years ago. I did notice an increase in my tendency to quickly take care of routine household, auto and personal maintenance chores I habitually tended to ignore, avoid or postpone.

I have taken Piracetam for eight years, Pramiracetam and Aniracetam for the past two years and Oxiracetam for about 9 months. During the past year, my lifelong severe writer’s block has gradually disappeared, and my writing output of the past year has exceeded that of the previous decade. Some studies on dementia comparing Piracetam and Oxiracetam (the two most nearly identical racetams). have suggested that Oxiracetam may be more effective in restoring the cognitive deficits of dementia (decreased memory, concentration and alertness), while Piracetam may be more effective at normalizing the emotional problems of dementia (agitation, tension-anxiety, hostility, insomnia, uncooperativeness).

Quantitatively, Piracetam is the least potent racetam, with clinical doses typically being 2400 mg to 4800 mg per day, occasionally even 6000 mg to I0,000 mg per day.

Oxiracetam is usually given 500 mg to 2400 mg per day. Aniracetam doses are typically 750 mg to 1500mg per day, while Pramiracetam has shown benefit even at 150 mg to 500 mg per day, although 600 mg to 1500 mg per day is more typical.

Piracetam and Oxiracetam are highly water soluble (96-98%), while Aniracetam and Pramiracetam are more fat soluble. Their lipophilicity may allow for less frequent dosing (once or twice daily) with Aniracetam and Pramiracetam, compared to 3 to 4 doses a day with Piracetam and Oxiracetam.

Aniracetam is favored by the Japanese, who have contributed much research on it. It is widely used there as an agent to rapidly promote clarity of thought.

Nootropics - uses and conclusion

During the past 30 years, the Piracetam-nootropics have been used to treat an amazingly broad range of human ailments and conditions, either or with other drugs, with moderate to major benefit. Piracetam-nootropics have been used to treat various forms of dementia and “organic brain syndrome.” They have been used successfully to treat dyslexia, epilepsy and age-associated memory impairment. Piracetam-nootropics have successfully treated post-concussional syndrome, vertigo, alcohol withdrawal, cerebrovascular insufficiency and hypoxia. They have shown benefit in normalizing blood flow parameter creased platelet aggregation, increased red blood cell (RBC) deformability, decreased adherence of damaged and sickle cell RBC’s dothelium (blood cell lining) and increased Prostacyclin (PG12) production and activity.

Yet the most exciting potential benefits of the racetams have yet seriously explored in clinical studies.

The racetams are cerebral homeostatic normalizers, neuroprotectants, cerebral metabolic enhancers and brain integrative agents. They enhance brain energy, especially under deficit condition: hypoxia, chemical toxicity or impaired cerebral microcirculation. They preserve, protect and enhance synaptic membrane and receptor structure and plasticity.

They enhance brain integration- horizontally, by increased coupling of the cerebral hemispheres; and vertically by enhancing cerebral connection with and tonic control of the limbic system, through nootropics effects on the hippocampus- a major link between cerebrum and system.

This vertical integration increase may help to integrate reason (cerebrum and emotion (limbic system- sometimes called the “horse brain”). The increased tonic cortico-subcortical control and regulation me prevent our limbic passions and desires from “running away with us” as in crimes of passion.

In middle aged and older individuals who do not yet suffer any specific neural malady or major mental impairment, nootropics may not only slow down or postpone entropic brain aging, but they may even reverse mild neural/ mental decline. Thus a person at 50 might be smarter, have better memory, quicker reflexes and greater vigilance and alertness than when they were 40. The racetams may literally be safe and effective pharmacologic tools to enhance, protect and optimize truly normal, fully human neuropsychological structures and function, well into old age.

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Oepen G, Eisele K, Thoden U, Birg W.

Pharmacopsychiatry 1985 Nov;18(6):343-6

Abstract

The influence of piracetam on Parkinsonism was studied in 18 patients and 18 matched controls. Clinical, visuomotor and psychometric variables were measured. Piracetam improved visuomotor reaction time (RT) and accuracy in 6 mildly affected and tracing time in 6 moderately affected patients, the clinical condition and the organic brain syndrome in all patients investigated. The improvement of the prolonged RT seems to be correlated with bradyphrenia. No drug influence could be observed in the prolonged interhemispheric transfer time. As the mildly affected patients displayed the clearest effect of piracetam, its administration in early and mild stage of Parkinsonism is recommended.

Obeso JA, Artieda J, Luquin MR, Vaamonde J, Martinez Lage JM.

Clin Neuropharmacol 1986;9(1):58-64

Abstract

Five patients with myoclonus were treated with oral piracetam (8-9 g/day). All patients had action-sensitive and/or stimulus-sensitive myoclonus and enhanced amplitude of somatosensory evoked potentials. Piracetam produced a marked reduction of the myoclonus in the five subjects without side effects. In view of its excellent tolerance and synergism with other anti-myoclonic drugs, we consider piracetam to be a very valuable drug for the treatment of patients with myoclonus of any origin.

Mindus P, Cronholm B, Levander SE, Schalling D.

Acta Psychiatr Scand 1976 Aug;54(2):150-60

Abstract

A double-blind, intra-individual cross-over comparison of the mental performance of 18 aging, non-deteriorated individuals during two 4-week periods of piracetam and placebo administration was performed using conventional and computerized perceptual-motor tasks. In a majority of these tasks the subjects did significantly better when on piracetam than on placebo, a finding consistent with ratings completed by two independent observers. The findings indicate new avenues for the treatment of individuals with reduced mental performance possibly related to disturbed alertness–a neglected group of psychiatric conditions.

Dimond SJ, Scammell RE, Pryce IG, Huws D, Gray C.

Psychopharmacology (Berl) 1979 Sep;64(3):341-8

Abstract

A study is described of effects of piracetam on chronic schizophrenia. Piracetam acts on the central nervous system with the cerebral cortex as their target. Chronic schizophrenic patients on the drug showed improvement in object naming and in tests where the patient was required to indicate the number of times he had been tapped. Improvements were also noted in learning and memory tasks. In dichotic listening the patients showed a reduction in the amount of incorrect verbal responses produced. There were no improvements in symptom rating or social behaviour rating. These results suggest some cognitive improvement but little if any change in the disease state of the patient.

Andreas K.

Institute of Pharmacology and Toxicology,
Medical Academy Carl Gustav Carus Dresden,
Federal Republic of Germany.
Naunyn Schmiedebergs Arch Pharmacol 1993 Jan;347(1):79-83

Abstract

The hexachlorophene-induced cytotoxic brain oedema is used as experimental model of brain damage, suitable for testing cerebroprotective substances. It has clinical importance since many brain injuries are accompanied by an oedema. The primary target of the neurotoxin, hexachlorophene, is the neuronal cell membrane, but it also causes secondary effects including a disruption of myelin lamellae, increases in water and sodium content, decreases of potassium content, and vacuolation in the white matter. Rats received orally hexachlorophene 240 mg/kg a day for three weeks by liquid diet. The disruption of coordinative motor response, observed in a specially developed test, was used to characterise hexachlorophene-induced injuries in studies designed to evaluate the potential of cerebroprotective substances. Because of their membranotropic efficacy some nootropic substances with different modes of action were examined. The disturbance of coordinative motor response was restored significantly earlier than in spontaneous remission following administration of piracetam, pyritinol, methyl glucamine orotate, naftidrofuryl, and also under the influence of the calcium antagonists cinnarizine, flunarizine and nifedipine. These results support the therapeutic use of nootropic substances in the management of neurotoxic injuries and brain oedema.

Szirmai A.

Department of Oto-Rhino-Laryngology,
Head and Neck Surgery,
Semmelweis University Medical School,
Budapest, Hungary.
Eur Arch Otorhinolaryngol 1997;254 Suppl 1:S55-7

Abstract

Vestibular symptoms frequently occur in patients with migraine headache. The common migraine is defined in neurology as a unilateral, pulsating headache, which may be associated with nausea and vomiting, and lasts one or several days. In the classic form patients have visual prodromal symptoms. Focal neurological signs in the migraine complique include, for example, oculomotor palsy and vestibular abnormalities. This so-called vestibular migraine is different from basilar migraine, which involves the irritation of the cervical sympathetic system, and can cause symptoms that resemble transient brainstem ischemia. In order to evaluate vestibular dysfunction electronystagmography (ENG) was used. Patients frequently had abnormal caloric test responses, especially with a directional preponderance, and most had a spontaneous nystagmus. In the migraine attack the patients are presumed to have hypersensitivity of the labyrinth with nausea and vomiting, while in the headache-free period the ENG was almost normal. At present, we have had a high success rate in treating patients with piracetam. Diazepam was used to treat basilar migraine and flunarizine to prevent vestibular migraine.

Dimond SJ, Brouwers EM.

Psychopharmacology (Berl) 1976 Sep 29;49(3):307-9

Abstract

Piracetam, a drug reported to facilitate learning in animals was tested for its effect on man by administering it to normal volunteers. The subjects were given 3×4 capsules at 400 mg per day, in a double blind study. Each subject learned series of words presented as stimuli upon a memory drum. No effects were observed after 7 days but after 14 days verbal learning had significantly increased.

Maritz NG, Muller FO, Pompe van Meerdervoort HF.

S Afr Med J 1978 Jun 3;53(22):889-91

Abstract

This article is a preliminary report of a new indication for the drug piracetam. It was found that piracetam was useful for the control of spasticity in 8 out of 16 patients with cerebral palsy. Side-effects were minimal.